CN111087426B - Demethylated anethol trithione derivative and preparation method and application thereof - Google Patents
Demethylated anethol trithione derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a demethylated anethol trithione derivative, a preparation method and application thereof. The demethylanethol trithione derivative is a compound shown as a formula (I). Wherein R is1、R2Independently or simultaneously selected from H, alkali metal cations or organic amine cations; x is selected from O, S or S ═ O. The compound has good water solubility, and has excellent effects in preventing and treating xerostomia syndrome, fatty liver, drug-induced liver disease, alcoholic liver disease, acute alcoholism, cerebral ischemia, cardiac ischemia and other diseases; the compound can be used for preparing medicines for treating the diseases and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a demethylated anethol trithione derivative, and a preparation method and application thereof.
Background
Xerostomia is a condition caused by lack of saliva in the oral cavity. Dry mouth is the main manifestation, bitter mouth, inflexible tongue movement, dysphagia, dry and cracked lips, scales, easy chap of corners of mouth and severe progressive dental caries. It is also accompanied by dry skin, dry eye, dry throat, and dry nasal cavity. The skin of half patients is dry, scales and itching feel exist, and the tongue is tinea due to scratching; dry eyes without tears, conjunctival congestion, dry cornea; atrophy of the mucous membrane of the upper respiratory tract and dryness and nodulation of the nasal mucous membrane. Clinically, xerostomia is very common, particularly, the incidence rate of the elderly and chemotherapy patients is higher, the patients are very painful in the course of disease, and the medicines for relieving the diseases are few, so that the medicines for preventing and treating the xerostomia belong to the clinical unmet requirements.
Fatty liver is a common liver disease, which refers to the accumulation of fat in liver cells caused by various causes, and is called fatty liver when the fat content exceeds 5% of the liver weight (wet weight) or 30% of the liver parenchyma histologically. Fatty liver can be classified into stage 3, stage I is simple fatty liver, stage II is steatohepatitis, about 10% of fatty liver is converted into stage III, and stage III is steatofibrosis and cirrhosis. Fatty liver is the second most serious liver disease in China, and the incidence rate is steadily increasing. More fatty liver disease people in Europe and America than hepatitis patients are also one of ten common causes of death, and in short, the fatty liver becomes a serious problem threatening the life and health of human beings, and the medicine for preventing and treating the fatty liver is also an unmet clinical demand.
Drug-induced liver disease refers to a disease caused by direct or indirect damage of certain drugs to the liver. Liver damage due to drugs or/and their metabolites. Can be used for treating liver damage of different degrees after a certain medicine is taken by healthy people without liver disease history or patients with serious diseases. At present, more than 600 drugs can cause the liver diseases, and the liver diseases have the same expression as the human liver diseases, and can be expressed as hepatocyte necrosis, cholestasis, intracellular microdroplet deposition or chronic hepatitis, liver cirrhosis and the like.
Alcoholic liver disease (Alcoholic Hepatitis) is a liver disease caused by prolonged heavy drinking. Early stages usually manifest as fatty liver, which may progress to alcoholic hepatitis, liver fibrosis and cirrhosis. Its main clinical features are nausea, vomiting, jaundice, possibly swollen liver and tenderness. And can be complicated with liver failure and upper gastrointestinal hemorrhage. Extensive hepatocellular necrosis, and even liver failure, can be induced by severe alcohol abuse. Alcoholic liver disease is one of the common liver diseases in China, and seriously harms the health of people. In recent years, the proportion of alcoholic liver diseases to hospitalized patients with liver diseases at the same time is increasing, and medicines for preventing and treating the alcoholic liver diseases are clinically unmet.
Alcoholism is commonly called drunkenness, and refers to abnormal body function state caused by drinking a large amount of alcohol (ethanol) once, and the most serious damage to nervous system and liver is caused. Medically, the acute poisoning and the chronic poisoning are classified, and the acute poisoning and the chronic poisoning can cause great harm to patients in a short time and can even directly or indirectly cause death. China is a big drinking country, documents report that acute alcoholism patients in China account for 0.5 percent of contemporary emergency patients and 49 percent of contemporary emergency patients, and medicines for treating acute alcoholism belong to clinical unmet requirements.
Cardiovascular and cerebrovascular diseases are the general names of cardiovascular diseases and cerebrovascular diseases, and generally refer to ischemic or hemorrhagic diseases of heart, brain and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension and the like. Cardiovascular and cerebrovascular diseases are common diseases seriously threatening the health of human beings, particularly middle-aged and elderly people over 50 years old, and have the characteristics of high morbidity, high disability rate and high mortality. At present, the treatment means of cardiovascular and cerebrovascular diseases are various, but even the most advanced and perfect treatment means are applied at present, more than 50 percent of the life of the heart cerebrovascular accident survivors can not be managed by oneself completely. According to statistics, the number of people dying from cardiovascular and cerebrovascular diseases every year in the world is as high as 1500 thousands of people, and the people live at the first position of various causes of death.
Disclosure of Invention
In order to solve the problems, the invention provides a demethylated anethol trithione derivative, a preparation method and application thereof.
The invention provides a compound shown as a formula (I):
wherein,
R1、R2independently or simultaneously selected from H, alkali metal cations or organic amine cations;
x is selected from O, S or S ═ O.
Further, R1、R2Independently or simultaneously selected from H or an alkali metal cation; the alkali metal cation is lithium ionSeed, potassium ion, sodium ion.
Further, the compound is:
further, R1、R2Are each selected from H or an organic amine cation, and R1、R2Not H at the same time; the organic amine cations are shown below:
wherein R is3、R4、R5、R6Separately or simultaneously selected from H, C1～C6Alkyl group, (CH)2)m-OH、
Or
m is an integer of 1 to 6, and n is an integer of 1 to 6.
Further, the compound is:
the invention also provides application of the compound in preparing a medicament for preventing and/or treating xerostomia, liver disease, acute alcoholism or cardiovascular and cerebrovascular diseases.
Further, the liver disease is fatty liver, drug liver disease or alcoholic liver disease; and/or, the cardiovascular and cerebrovascular diseases are cerebral apoplexy or myocardial ischemia.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Further, the pharmaceutically acceptable adjuvant is selected from any one or more of diluents, fillers, colorants, glidants, lubricants, binders, stabilizers, suspending agents or buffers.
Further, the preparation is a tablet, a capsule, an oral liquid, an injection, a transdermal agent, an aerosol solid preparation, a liposome preparation or a sustained and controlled release preparation; preferably, the preparation unit contains 5-200mg/kg of the compound.
In the invention, the room temperature is 25 +/-5 ℃; the overnight period was 12. + -.2 h.
In the present invention, the minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix Ca～CbAlkyl denotes any alkyl group containing "a" to "b" carbon atoms, thus, for example, C1～C6The alkyl group means an alkyl group having 1 to 6 carbon atoms.
The compound has good water solubility, and has excellent effects in preventing and treating xerostomia syndrome, fatty liver, drug-induced liver disease, alcoholic liver disease, acute alcoholism, cerebral ischemia, cardiac ischemia and other diseases; the compound can be used for preparing medicines for treating the diseases and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a mass spectrum of compound I-1-2 of the present invention.
FIG. 2 is a bar graph of the NSS score of experimental cerebral ischemia damaged rats with the compound of the present invention.
FIG. 3 is a histogram of TTC staining measurements of groups to detect cerebral infarction volume of experimental rats.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Unless otherwise specified in the following examples, the methods employed are conventional in the art.
Example 1 preparation of demethylanethole trithione (ADT)
20g of anethol trithione (M1) and 58 g of anhydrous pyridine hydrochloride are uniformly mixed, slowly heated to 220 ℃ under the protection of nitrogen, the solid is completely dissolved into a homogeneous system, the temperature is maintained at 220 ℃, the stirring is continued for 30 minutes, and the mixture is naturally cooled to the room temperature. Adding 200ml ethyl acetate and 200ml water, heating to 50 ℃, stirring for 30 minutes, filtering to remove insoluble substances, standing and demixing the obtained filtrate, taking an ethyl acetate layer, respectively washing with 40ml clear water twice, adding 50g anhydrous sodium sulfate and 5 g activated carbon, drying and decoloring overnight. The next day, sodium sulfate and activated carbon were removed by filtration, and when the solution was concentrated to precipitate a solid, 50ml of petroleum ether was added and the mixture was crystallized by stirring. After crystallization is complete, 12g of an orange-yellow solid is obtained by filtration. The yield thereof was found to be 63.7%.
1HNMR(DMSO，400MHz)：δppm：7.77(m，2H)，7.69(m，1H)，6.90(m，2H)。
EXAMPLE 2 preparation of Compound I-1-1 of the present invention
Dissolving 20g of demethylated anethol trithione (ADT) by using 200ml of dichloromethane, adding 21 g of pyridine, cooling to the temperature below-10 ℃, slowly dropwise adding 27 g of phosphorus oxychloride, reacting for 5 hours at the temperature of-5-0 ℃ after completing dropwise adding of the phosphorus oxychloride, and completely reacting for demethylated anethol trithione. 200ml of ice water is added, the mixture is stirred for half an hour and then is kept stand, and the crude compound I-1-1 is precipitated at the bottom of a bottle as oil. The water and dichloromethane were decanted off and the residual oil was washed 2 times with 40ml of 1N hydrochloric acid respectively to remove pyridine hydrochloride. After the hydrochloric acid was poured off, the resulting product was dissolved in 100ml of tetrahydrofuran, and dried over 30 g of anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the tetrahydrofuran was concentrated to dryness to give 24 g of the compound I-1-1 in 88.6% yield.
ESI m/z：349.89[M+2Na+]。
Example 3 preparation of Compounds I-1-2 and I-1-3 of the invention
12g of the compound I-1-1 was dissolved in 30ml of absolute ethanol, and a saturated solution of sodium methoxide in methanol was slowly dropped while stirring at room temperature until the pH was about 7.5, and about 2.5 g of sodium methoxide was consumed. After the dropwise addition, the mixture is stirred for 30 minutes at room temperature, filtered and dried to obtain a reddish brown solid, namely 11 g of a crude product of the compound I-1-2, with the yield of 80%.
And heating 11 g of the crude product of the I-1-2 with 44 g of purified water to 70 ℃ for dissolution, naturally cooling to room temperature, slowly adding 88 g of absolute ethyl alcohol to crystallize and separate out, continuously stirring for 1 hour, filtering, and drying to obtain 7 g of a light red solid of the compound I-1-2 with the yield of 63.6%. The mass spectrum of the compound I-1-2 of the invention is shown in figure 1.
ESI m/z：394.00[M+2Na+]。
1HNMR(DMSO，400MHz)：δppm：7.8(m，2H)，7.7(m，1H)，7.36(m，2H)。
As in this example, consumption of sodium methoxide 1.25 g gave rise to the monosodium salt of nor-anethol trithiophosphate, which was compound I-1-3 of the present invention, as a pale red solid, 6.7 g.
Example 4 preparation of Compounds I-1-4 of the invention
Dissolving 3 g of the compound I-1-2 with 10ml of purified water at room temperature, cooling to the internal temperature of 0 ℃, slowly dropwise adding 3.5 g of 10% hydrogen peroxide, keeping the internal temperature of 0 ℃, stirring for 1 hour, adding sufficient ethanol for quenching, filtering, and drying to obtain 2.5 g of the compound I-1-4 dark yellow solid with the yield of 79.7%.
ESI m/z：411.84[M+2Na+]。
EXAMPLE 5 preparation of Compounds I-1-5 of the invention
Dissolving 3 g of the compound I-1-2 with 10ml of purified water at room temperature, cooling to the internal temperature of 0 ℃, slowly dropwise adding 14.5 g of 10% hydrogen peroxide, keeping the internal temperature of 0 ℃, and stirring overnight. After the reaction is completed, sufficient ethanol is added for quenching, filtering and drying are carried out, and 2.4 g of compound I-1-5 dark yellow solid is obtained with the yield of 84%.
ESI m/z：379.92[M+2Na+]。
1HNMR(DMSO，400MHz)：δppm：7.76(dd，J＝8.8,3.3Hz,2H)，7.67(d，J＝3.5Hz,1H)，7.34(dd，J＝3.2Hz,2H)。
EXAMPLE 6 preparation of a pharmaceutical tablet composition of the Compound of the invention
The pharmaceutical tablet composition of the compound I-1-1 comprises 1 part by weight of the compound I-1-1, 0.1-0.5 part by weight of lactose, 0.05-0.08 part by weight of hydroxypropyl cellulose, 0.008-0.014 part by weight of sodium carboxymethyl starch, a proper amount of povidone K30 and 0.01-0.05 part by weight of magnesium stearate; tablets containing 50 mg of compound I-1-1 per tablet were prepared according to the above ratio.
The preparation method of the medicinal tablet composition of the compounds I-1-2, I-1-3, I-1-4 and I-1-5 is the same as that described above.
EXAMPLE 7 preparation of a pharmaceutical Capsule composition of the Compound of the present invention
The medicinal capsule composition of the compound I-1-2 comprises 25 g of the compound I-1-2, 171 g of lactose and 4 g of aerosil, and the total amount is 200 g and a No. 2 empty capsule. The preparation method comprises the following steps:
a, mixing the compound I-1-2, lactose and aerosil by using a conventional method to obtain mixed powder;
and b, sieving the mixed powder by a 120-mesh sieve, filling into No. 2 capsules, sealing, and preparing into 1000 granules.
Wherein each capsule contains 25 mg of compound I-1-2.
The preparation method of the medicinal capsule composition of the compounds I-1-1, I-1-3, I-1-4 and I-1-5 is the same as that described above.
EXAMPLE 8 preparation of a Compound of the present invention for pharmaceutical injection composition
A pharmaceutical injection composition of compound I-1-2, comprising 100g of I-1-2, 34 g of disodium hydrogenphosphate and a sufficient amount of water for injection. The preparation method comprises the following steps:
dissolving disodium hydrogen phosphate and I-1-2 by using carbon dioxide saturated injection water, and preparing 2000ml by using the carbon dioxide saturated injection water;
b, filtering the solution obtained in the step a, subpackaging the filtered solution into 1000 bottles of 2ml ampoules, and sealing the ampoules by melting;
and c, sterilizing the ampoule bottle obtained in the step b by circulating steam, and checking.
The preparation method of the medicinal injection composition of the compounds I-1-3, I-1-4 and I-1-5 is the same as that described above.
The advantageous effects of the present invention are demonstrated by specific test examples below.
Test example 1 Compounds of the present invention increase salivary flow in rat xerostomia syndrome
Wistar rats, male, weighing 220- & 250g, were provided by Soudouche laboratory animals GmbH, totaling 42. Rats were randomly grouped (2 of them were reserved for antigen preparation) into 8 per group, respectively: blank control group, molding normal saline group, compound I-1-2, compound I-1-4, and compound I-1-5 administration group.
Preparation of antigen: and (3) homogenizing the submaxillary gland tissue of the rat on ice, and fully and uniformly mixing the homogenate with Freund complete adjuvant (CFA) with the same volume for emulsification to obtain the emulsified protein antigen (the mass concentration is 600 mu g/ml).
Modeling of rat xerostomia syndrome: the rats of the molding normal saline group and the administration group are subjected to molding treatment, and emulsified protein antigens are injected into two hind soles and two lateral groins of the rats at multiple points respectively, wherein the total dose of each rat is l ml. At 21 st and 35d after the first immunization, the immunization is strengthened by emulsified self-submandibular gland protein antigen for 2 times, and the vaccine of 0.2ml is respectively injected to the back of each mouse at 1 st, 7 th, 21 th and 35 th days after the induction of the autoimmune response for 4 times to strengthen the immune response. The blank control was not molded.
Administration to each group: after 7 weeks of immunization, the blank control group and the molding normal saline group are each orally administrated with gastric lavage normal saline 1 ml/day; the three administration groups respectively take the intragastric gavage compounds I-1-2, I-1-4 and I-1-5 orally, the dosage is 10 mg/kg/day, the compounds I-1-2, I-1-4 and I-1-5 are prepared by normal saline, and the intragastric gavage volume is 1 ml. The dosing period was 6 weeks.
Calculating the saliva flow: according to the formula: saliva flow (mg) is cotton ball wet weight-cotton ball dry weight, and the saliva flow of each group of rats in the resting state is measured for 10min, and the specific method comprises the following steps: picking up the cotton ball with elbow forceps, weighing the cotton ball with mass M0, placing under the tongue of the rat, fixing the cotton ball with forceps, and measuring the mass of the cotton ball after 10min to obtain the mass M1, (M1-M0) which is the salivary flow of the rat.
As shown in Table 1, the compounds I-1-2, I-1-4 and I-1-5 of the present invention significantly increased salivary flow 6 weeks after administration (compared with the molding saline solution group,**p < 0.001), showing an effect of improving xerostomia syndrome.
TABLE 1 Compounds of the invention increase salivary flow in laboratory rats
| Group of | Saliva flow rate (mg) of rat |
| Blank control group | 35.6±2.3 |
| Molding physiological saline solution set | 27.4±1.9 |
| Group I-1-2 | 34.8±1.7** |
| Group I-1-4 | 33.2±2.0** |
| Group I-1-5 | 34.1±1.9** |
Test example 2 animal Experimental study on prevention and treatment of fatty liver by Compound of the present invention
A selection of 120 male Wistar rats weighing 180-220g was provided by Soudouzhuoshu laboratory animals GmbH and divided into 6 groups of 20 rats. In the compound experiment, a proper amount of Tween is firstly used for grinding, and then 0.5 percent of sodium carboxymethylcellulose suspension (CMC) is prepared according to the design concentration.
After 3 days of acclimatization, the rats were administered 30mg/kg (formulated with an equivalent amount of 0.5% CMC suspension) of the compounds I-1-2, I-1-4, I-1-5 and metformin (metformin) daily in each group, and the blank and model groups were administered an equivalent amount of 0.5% CMC suspension. In the afternoon, except for the blank group, 10% CCl was intraperitoneally injected every other day into rats in each group4Rapeseed oil solution, the injection dose is: 0.08ml/100g, blank group was injected at the same site with equal volume of physiological saline.
Fasting for 16 hours (without water), weighing the animals, taking blood from femoral artery, centrifuging and separating serum, storing at-30 ℃ and testing biochemical indexes in the serum after the last administration on the 18 th day. Separately taking and weighing the liver, observing the outside of the body, and respectively placing 2 pieces of the left leaf of each liver in 10% neutral formalin solution for histopathological examination of the liver (after fixation, paraffin embedding, slicing, and respectively performing HE staining and fat staining).
Biochemical index of each group of rats is recorded in Table 2 below.
TABLE 2 Biochemical indices of serum of rats in each group
Note: comparison with metformin: p <0.01, P < 0.05.
The results of the liver histopathological examination analysis are shown in table 3 below.
TABLE 3 histopathological examination of the liver of rats in each group
Note: comparison with metformin: p <0.01, P < 0.05.
The results of the evaluation of liver fat staining are shown in table 4 below.
Table 4 results of liver fat staining in rats of each group
| Group of | Administration dose (mg/kg) | Scoring |
| Blank group | N/ |
0 |
| Model set | N/A | 2.4 |
| I-1-2 | 30 | 1.3* |
| I-1-4 | 30 | 1.0** |
| I-1-5 | 30 | 1.4* |
| metformin | 30 | 1.6 |
Note: comparison with metformin: p <0.01, P < 0.05.
The experiments show that the compound not only can obviously reduce biochemical indexes TG, CHOL, ALT and AST, but also has obvious improvement effect on pathological injury of the liver, particularly on hepatic cell steatosis.
Test example 3 protective action of Compound of the present invention on Alcoholic liver injury rat
SD rats, male, weighing 220-. After 7 days of adaptive feeding, fasting for 12 hours, randomized into 3 groups: blank control group 12, model group 12 and administration group 12. The blank control group is given conventional words and materials, and freely takes food and drinks water, and is given equal volume of normal saline by intragastric administration every day; the model group and the administration group were administered 56 degrees of high-alcohol drench daily, and the dose was increased with time, 8g/kg at week 1, 10g/kg at week 2, and 12g/kg at week 3 and the end of the test. The alcohol dose (g) × white spirit volume (ml) × white spirit volume fraction (0.56) × alcohol relative density. The administration group was also administered with gastric compound I-1-2 (prepared with normal saline at a dose of 30mg/kg) at the same time as the start of molding, and the groups were fed in the same manner until the end of the experiment. All animals were bled from the abdominal aorta after fasting for hours at week 24, and serum was removed after centrifugation to detect alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Malondialdehyde (MDA), and glutathione (glutathione). The results are shown in Table 5, after the compound I-1-2 is administrated, ALT, AST, MDA and GSH index abnormity caused by alcohol can be remarkably reduced, and the difference is remarkable compared with a model group (**P is less than 0.001), and the result shows that the compound has obvious protective effect on liver injury of rats caused by alcohol.
TABLE 5 influence of serum-related indices of alcoholic liver injury rats
| Group of | ALT(IU/L) | AST(IU/L) | MDA(nmol/ml) | GSH(mg/L) |
| Blank control group | 70.08±16.9 | 15.89±1.33 | 3.31±0.98 | 11.57±3.33 |
| Model set | 225.19±20.8 | 88.91±16.35 | 15.31±1.18 | 25.13±3.21 |
| Administration set | 120.03±11.85** | 36.23±17.95** | 6.21±2.52** | 14.59±4.22** |
Test example 4 protective Effect of the Compound of the present invention on drug-induced hepatic injury in rats
SD rats, male, weighing 220-. After 7 days of adaptive feeding, fasting for 12 hours, randomized into 3 groups: blank control group 12, model group 12 and administration group 12. The blank control group is given conventional words and materials, and freely takes food and drinks water, and is given equal volume of normal saline by intragastric administration every day; the model group and the administration group were administered with isoniazid at 75mg/kg daily for 14 days. The administration group was also administered with gastric compound I-1-2 (prepared with normal saline at a dose of 30mg/kg) at the same time as the start of molding, and the groups were fed in the same manner until the end of the experiment. Week 24All animals were bled from the abdominal aorta after fasting for hours, and serum was taken after centrifugation to detect alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Malondialdehyde (MDA), glutathione (glutathione, GSH). The results are shown in Table 6, after the compound I-1-2 is administrated, ALT, AST, MDA and GSH index abnormity caused by alcohol can be remarkably reduced, and the difference is remarkable compared with a model group (**P is less than 0.001), and the result shows that the compound has obvious protective effect on liver injury of rats caused by drugs.
TABLE 6 influence of serum-related indices of alcoholic liver injury rats
| Group of | ALT(IU/L) | AST(IU/L) | MDA(nmol/ml) | GSH(mg/L) |
| Blank control group | 67.78±17.4 | 16.21±2.33 | 3.55±1.03 | 12.31±2.32 |
| Model set | 263.01±23.1 | 113.19±15.41 | 21.00±1.68 | 32.07±3.13 |
| Administration set | 166.29±23.04** | 51.37±14.75** | 4.34±1.15** | 15.19±4.08** |
Test example 5 acceleration of acute alcoholism rat awakening by Compound of the present invention
SD rats, male, weighing 220-. After 3 days of adaptive feeding, fasting was performed for 12 hours, and the group was randomly divided into 2 groups, 12 each of the model group and the administration group. The model group rats were intragastrically administered with 75% ethanol at a dose of 10ml/kg, and the rats were administered with normal saline (500. mu.l) via tail vein when they were in an intoxicated state; the administration group rats were gavaged with 75% ethanol at a dose of 10ml/kg, and when an intoxication state occurred, compound I-1-2 was injected into the tail vein at a dose of 5mg/kg, compound I-1-2 was prepared with normal saline at an injection volume of 500. mu.l. Recording the drunk time and the sober-up time: inverting within 1min and reflecting for less than 3 times to determine drunk state; the sobering-up time is as follows: righting the reflection recovery time. The results are shown in Table 7, and Compound I-1-2 shortens the time interval from the intoxication state to the awakening state of the animals and has a significant antialcoholism effect as compared with the model group (**P＜0.001)。
Table 7 compounds of the invention shorten the time interval from intoxication to the awakening state in experimental rats
| Group of | Average wake time (h) |
| Model set | 8.3±2.2 |
| Administration set | 5.1±1.5** |
Test example 6 protective action of Compound of the present invention on rats injured by Experimental cerebral ischemia
Preparation of focal cerebral ischemia (MCAO) rat model by wire-embolism method: the method for manufacturing the mold according to the wire bolt is partially improved; 3.5mL/kg of 10% chloral hydrate is anesthetized by intraperitoneal injection, a rat is fixed on an operating table in a supine position, the rat is disinfected conventionally, a neck median incision is made, the right common carotid artery and the external carotid artery are exposed, vagus nerves accompanying the common carotid artery and the external carotid artery are carefully separated, the common carotid artery and the external carotid artery are ligated, the common carotid artery is cut by a small incision with an ophthalmic scissors about 0.5cm away from a bifurcation, a standby thread plug is sent into the incision and pushed inwards, the thread plug is led to the middle artery along the common carotid artery and the internal carotid artery, the thread plug is stopped when resistance is met, the insertion depth (1.8 +/-0.5) cm is calculated from the bifurcation of the common carotid artery, the blood supply of the middle cerebral artery of the rat is blocked, and the thread plug is removed after 1 hour.
Animal grouping: (1) a sham operation group; (2) ischemia reperfusion model group; (3) the compound I-1-2(10mg/kg) intervention group of the invention: preparing normal saline, immediately carrying out tail vein injection to give half dose after molding, and carrying out tail vein injection to give the remaining half dose 6 hours after pulling out the suppository thread; (4) compounds I-1-5(10mg/kg) of the present invention intervene group: preparing normal saline, immediately carrying out tail vein injection to give half dose after molding, and carrying out tail vein injection to give the remaining half dose 6 hours after pulling out the suppository thread; (5) edaravone (Edaravone) (6mg/kg) positive control group, prepared with normal saline, administered immediately after molding, and injected into tail vein; (6) an active control group of hydroxyanisole trithione (ADT) (10mg/kg) is prepared by dissolving corn oil, injecting half dose intraperitoneally after 3 hours of ischemia reperfusion, and injecting the remaining half dose intraperitoneally after 10 hours of ischemia reperfusion.
And respectively carrying out nerve function scoring after the model is built and 24 hours after the model is built, wherein the higher the score is, the more serious the nerve function damage is represented by adopting an NSS scoring method.
2,3, 5-triphenyltetrazolium chloride (TTC) staining measures cerebral infarct volume: the rat is killed by cutting off the head 25 hours after the ischemia brain tissue infarction rate is modeled, the brain is taken out quickly, the rat is placed in a refrigerator at the temperature of minus 20 ℃ for 10 minutes quickly after being washed by cold saline, the rat is taken out after the brain tissue is slightly hard, a olfactory bulb, a pituitary and a lower brainstem are cut off, the rat is sliced from the front to the back of the coronal direction, the rat is evenly sliced into brain slices with the thickness of 2mm, the brain slices are evenly sliced into 5 brain slices, the brain slices are placed in a 1% TTC solution, the rat is incubated for 30 minutes in a dark place at the temperature of 37 ℃, and the rat. TTC can react with dehydrogenase system in normal tissue and be reduced to rose red, so that normal tissue is dyed rose red, infarcted tissue is white and well-defined, the ophthalmic forceps can accurately peel off infarcted parts, the total weight is precisely weighed and recorded by an electronic balance, and the cerebral infarct volume is calculated.
The results show that: NSS scores prove that the injection of the compounds I-1-2 and I-1-5 of the invention reduces nerve defects of rats (figure 2), the improvement of nerve functions is better than that of a model group after 24h of model building, and the difference is obvious (P is less than or equal to 0.05); the results of measuring the cerebral infarction volume by TTC staining (figure 3) at 24h after molding prove that the compounds I-1-2 and I-1-5 of the invention obviously reduce the infarction volume, and have obvious difference (P is less than or equal to 0.05) compared with the model group.
From the data, compared with the reported hydroxyanisole trithione (ADT), the compound provided by the invention has the advantages of strong water solubility, simple and convenient preparation operation, stronger therapeutic effect under the same dosage and obvious difference (P is less than or equal to 0.05).
Test example 7 protective Effect of the Compound of the present invention on ischemia-reperfusion injury of rat Heart
After being adaptively fed for 1 week, 220-250g of healthy male SPF-grade SD rats are in a good state.
Rats were randomly divided into Sham (Sham) groups, cardiac ischemia reperfusion injury (MI/R) groups, and inventive compound pre-treatment groups (both MI/R and inventive compound pre-treatment groups were administered at a dose of 5mg/kg), 10 per group. The compound of the invention is injected into tail vein before the compound pretreatment group, and the MI/R group is administrated with equal volume amount of 0.900 sodium chloride solution before the MI/R group, and the heart ischemia reperfusion operation is administrated 14 days after the pretreatment group and the MI/R group are administrated; re-perfusing for 4h, re-ligating the left anterior descending branch of the coronary artery in situ, injecting Evans blue from the aorta, picking the heart after the non-ischemic region of the heart is dyed blue, rinsing with saline water at 4 ℃, slicing, dyeing and fixing TTC liquid, wherein the blue dyed region is the non-ischemic region, the red region (containing white region) is the ischemic region, and the white region is the infarct region; the area of each region was measured by Image ProPlus software, and the myocardial infarction area was expressed as infarct area/ischemic area X100%, and the results are shown in Table 8.
TABLE 8 protective Effect of the Compounds of the present invention on ischemia-reperfusion injury of rat heart
| Grouping | Dosage to be administered | Myocardial infarction area (%) |
| Sham | / | 0.7±0.2 |
| MI/R | / | 70.8±12.1 |
| Group I-1-2 | 5mg/kg | 52.6±3.7* |
| Group I-1-4 | 5mg/kg | 53.0±4.7* |
| Group I-1-5 | 5mg/kg | 50.9±4.1* |
As shown in Table 8, the compound of the present invention has obvious protective effect on rat cardiac ischemia reperfusion injury, and compared with MI/R group, the infarct size is obviously reduced, and the difference is obvious (*P≤0.05)。
In conclusion, the compound has better water solubility and has excellent effects in preventing and treating xerostomia syndrome, fatty liver, drug-induced liver disease, alcoholic liver disease, acute alcoholism, cerebral ischemia, cardiac ischemia and other diseases; the compound can be used for preparing medicines for treating the diseases and has good application prospect.
Claims (11)
1. A compound of formula (I):
wherein,
R1、R2independently or simultaneously selected from H, alkali metal cations or organic amine cations;
x is selected from O, S or S ═ O.
2. The compound of claim 1, wherein: r1、R2Independently or simultaneously selected from H or an alkali metal cation; the alkali metal cations are lithium ions, potassium ions and sodium ions.
3. The compound of claim 2, wherein: the compound is:
4. the compound of claim 1, wherein: r1、R2Are each selected from H or an organic amine cation, and R1、R2Not H at the same time; the organic amine cations are shown below:
wherein R is3、R4、R5、R6Separately or simultaneously selected from H, C1～C6Alkyl group, (CH)2)m-OH、
m is an integer of 1 to 6, and n is an integer of 1 to 6.
5. The compound of claim 4, wherein: the compound is:
6. use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the prophylaxis and/or treatment of dry mouth, liver diseases, acute alcoholism or cardiovascular and cerebrovascular diseases.
7. Use according to claim 6, characterized in that: the liver disease is fatty liver, drug-induced liver disease or alcoholic liver disease; and/or, the cardiovascular and cerebrovascular diseases are cerebral apoplexy or myocardial ischemia.
8. A pharmaceutical composition characterized by: the compound is a preparation prepared by taking the compound as an active ingredient according to any one of claims 1 to 5 and adding pharmaceutically acceptable auxiliary materials.
9. The pharmaceutical composition of claim 8, wherein: the pharmaceutically acceptable auxiliary materials are selected from any one or more of diluents, fillers, colorants, glidants, lubricants, binders, stabilizers, suspending agents or buffering agents.
10. The pharmaceutical composition of claim 8, wherein: the preparation is tablet, capsule, oral liquid, injection, transdermal agent, aerosol solid preparation, liposome preparation or sustained and controlled release preparation.
11. The pharmaceutical composition of claim 10, wherein: said formulation containing 5-200mg/kg of a compound according to any one of claims 1-5.
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| WO2009065926A2 (en) * | 2007-11-22 | 2009-05-28 | Sulfidris S.R.L. | New anticancer compounds |
| CN101618222A (en) * | 2008-06-30 | 2010-01-06 | 成都国嘉联合制药有限公司 | Anethol trithione and phospholipid compound and preparation method thereof |
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| WO2009065926A2 (en) * | 2007-11-22 | 2009-05-28 | Sulfidris S.R.L. | New anticancer compounds |
| CN101618222A (en) * | 2008-06-30 | 2010-01-06 | 成都国嘉联合制药有限公司 | Anethol trithione and phospholipid compound and preparation method thereof |
| CN102690316A (en) * | 2012-06-13 | 2012-09-26 | 中国药科大学 | Preparation method of glycyrrhetinic acid derivative and medical application thereof in serving as liver-protective medicament |
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